Biosensor-regulated Gene Therapy Reduces Heart Attack Damage In Mice

M. Ian Phillips, PhD, DSc, and his team at the USF College of Medicine and All Children's Hospital Research Institute designed a kind of oxygen-sensitive biosensor that turns on protective genes when signs of oxygen deprivation indicate a heart attack and turns the genes off once blood flow restores adequate oxygen levels to the heart. Dr. Phillips, principal investigator; Yao Liang Tang, MD, lead author; and colleagues showed that this biosensor-regulated gene therapy protected heart muscle cells in mice with heart attacks from further injury.

Dr. Phillips and Dr. Tang envision administering such a therapy after a first heart attack to limit initial damage and prevent future attacks. While much work remains to test and refine such a therapy, Dr. Phillips said, this new concept might eventually be an alternative to stents and bypass surgery.

People who suffer one heart attack are at higher risk for subsequent attacks. Often lack of blood flow to the heart muscle, known as cardiac ischemia, does not cause pain or other symptoms. This asymptomatic or "silent" ischemia can lead to a second or third heart attack without prior warning.

"Repeated bouts of myocardial ischemia cause cumulative tissue damage in the heart vessels that can lead to a fatal heart attack," said Dr. Phillips, USF vice president for research and professor of physiology and biophysics. "Therefore, what patients need is a gene therapy strategy that acts in the heart and switches on or off, so that the therapeutic protein is produced only where and when it is needed."

"One of the exciting aspects of the approach, described by Tang et al, is the ability to directly link expression of potentially therapeutic genes to a pathological stimulus associated with myocardial infarction, ischemia," states an editorial in Hypertension highlighting the USF research. "Ultimately, this area of research will pave the way for development of 'smart' therapies for the heart that allow for early and rapid treatment of a wide variety of cardiac ailments."

The USF researchers designed a molecule -- which they call a "vigilant vector" -- containing both a means to increase the expression of protective heme oxygenase-1(HO-1) genes and the oxygen-sensitive switch that turns these genes on and off. They injected this molecule directly into the hearts of mice one hour after the mice had heart attacks.

Ten days following their heart attacks, the mice that received the biosensor-regulated gene therapy showed less heart tissue scarring and better recovery of heart pumping function than the untreated mice injected with saline only. The researchers demonstrated that turning on the protective HO-1 genes stopped the heart muscle cells from dying and limited the area of damage.